A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant ca...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2013
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| _version_ | 1826272646748176384 |
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| author | Vester, A Velez-Ruiz, G McLaughlin, H Nisc, C Lupski, JR Talbot, K Vance, J Züchner, S Roda, R Fischbeck, K Biesecker, L Nicholson, G Beg, A Antonellis, A |
| author_facet | Vester, A Velez-Ruiz, G McLaughlin, H Nisc, C Lupski, JR Talbot, K Vance, J Züchner, S Roda, R Fischbeck, K Biesecker, L Nicholson, G Beg, A Antonellis, A |
| author_sort | Vester, A |
| collection | OXFORD |
| description | Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed. © 2012 Wiley Periodicals, Inc. |
| first_indexed | 2024-03-06T22:15:52Z |
| format | Journal article |
| id | oxford-uuid:535f8593-5f85-48f2-a77b-0d631344d0e3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:15:52Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:535f8593-5f85-48f2-a77b-0d631344d0e32022-03-26T16:31:14ZA Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In VivoJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:535f8593-5f85-48f2-a77b-0d631344d0e3EnglishSymplectic Elements at Oxford2013Vester, AVelez-Ruiz, GMcLaughlin, HNisc, CLupski, JRTalbot, KVance, JZüchner, SRoda, RFischbeck, KBiesecker, LNicholson, GBeg, AAntonellis, AAminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed. © 2012 Wiley Periodicals, Inc. |
| spellingShingle | Vester, A Velez-Ruiz, G McLaughlin, H Nisc, C Lupski, JR Talbot, K Vance, J Züchner, S Roda, R Fischbeck, K Biesecker, L Nicholson, G Beg, A Antonellis, A A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title | A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title_full | A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title_fullStr | A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title_full_unstemmed | A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title_short | A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo |
| title_sort | loss of function variant in the human histidyl trna synthetase hars gene is neurotoxic in vivo |
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